Three approaches were taken to address the mechanism of cellular transformation induced by nonreceptor protein-tyrosine kinases. One involves overexpression of fgr genes specifying normal or aberrant kinases in NIH/3T3 cells. Our findings document a rare malignant transformation by high levels of p55-c-fgr. Furthermore, it was shown that by mutation of sequences encoding the carboxyl terminus of p55-c-fgr the c-fgr gene is converted into a potent, dominant acting oncogene. A search for substrates for these activated tyrosine kinases has identified molecules of 135 kd and 70 kd that preferentially interact with and are tyrosine phosphorylated by transforming as compared to normal versions of src, fyn, and fgr kinases. The third approach involves searching for evidence of activated tyrosine kinases in naturally occurring human neoplasia, especially squamous cell carcinomas of the head and neck. We have found that the receptor for epidermal growth factor is activated in a majority of oral squamous cell carcinomas and have identified a novel mechanism for activation of this receptor.